INHIBITION OF HUMAN-IMMUNODEFICIENCY-VIRUS TYPE-1 REPLICATION BY PHOSPHONOFORMATE AND PHOSPHONOACETATE-2',3'-DIDEOXY-3'-THIACYTIDINE CONJUGATES

The synthesis of potential ''combined prodrugs'' where phosphonoformic acid (PFA) or phosphonoacetic acid (PAA) was attached to the 5'-O or N-4 position of 2',3'-dideoxy-3'-thiacytidine (BCH-189) is described. The anti-HIV-1 activity of 11 analogues which included carboxylic este r or phosphoric ester linkages of PFA or PAA to BCH-189 was determined in MT-4 cells. Of these compounds, the IC50 Of analogues 3, 4, 6, and 7 ranged from 0.2 to 100 mu M, while IC50 for BCH-189 in this system was 0.1 mu M. In vitro hydrolysis of the various esters or amides in h uman plasma indicated that these agents were relatively stable in the presence of plasma esterases with t(1/2) values of up to 120 min. More over, lipophilicity of these compounds (partition coefficient) was det ermined in order to establish correlation between lipophilicity and di ffusion of BCH-189 analogues into the cells. The active compounds may exert their effects by extracellular or intracellular hydrolysis to th e corresponding antiviral agent BCH-189, but intrinsic anti-HIV-1 acti vity of some of PAA and PFA adducts, themselves, may also be involved.